The present invention relates to an indole derivative and a mono- or diazaindole derivative that show an anti-inflammatory action and so forth and are useful as pharmaceuticals.
At present, the majority of medicines widely used as anti-inflammatory agents are non-steroid anti-inflammatory drugs (NSAIDs) that have, as the mechanism of action, an inhibitory action on cyclooxygenase (COX) that is involved in the biosynthesis of prostaglandin E2 (PGE2). However, since PGE2 synthesis activity is present in various tissues in the living body and governs the homeostasis thereof, various side effects are induced when NSAID is administered. For example, PGE2 demonstrates the action of maintaining blood flow in the stomach and kidneys, whereas administration of NSAIDs makes it difficult to maintain local blood flow, thereby causing gastric or renal disorders.
Under such circumstances, the presence of a COX isozyme has been confirmed. In order to distinguish it from the previously identified COX, the conventional type has been named COX-1, while the newly discovered isozyme has been named COX-2. In addition, this COX-2 has been clarified to be induced during inflammation and hardly be expressed at all under normal circumstances. It was also clarified that conventional NSAID are able to non-specifically inhibit both COX-1 and COX-2 enzymes. Therefore, the possibility arose of a compound having COX-2 inhibitory action being useful as a novel anti-inflammatory agent.
There are currently several compounds that are known to selectively inhibit only COX-2 without inhibiting COX-1 (Inflammation and Immunology, 3 (1), 29-36, 1995; Bioorganic and Med. Chem. Lett. 5 (8), 867-872, 1995, etc.). However, the actions of these compounds are not satisfactory and since some of them do not have an adequate water solubility or oral absorption, there is a need for a drug that demonstrates more effective COX-2 inhibitory action.
In addition, an indole derivative represented by the following formula: 
(wherein, Ra represents a hydrogen atom, a straight or branched alkyl group having 1 to 7 carbon atoms, a straight or branched alkenyl group having 2 to 7 carbon atoms, a straight or branched alkynyl group having 2 to 7 carbon atoms, a cycloalkenyl group having 4 to 6 carbon atoms, an aryl group, a heteroaryl group, an alkylcarbonyl group in which the alkyl moiety is a straight or branched alkyl group having 1 to 7 carbon atoms, an alkenylcarbonyl group in which the alkenyl moiety is a straight or branched alkenyl group having 2 to 7 carbon atoms, an alkynylcarbonyl group in which the alkynyl moiety is a straight or branched alkynyl group having 2 to 7 carbon atoms, or xe2x80x94(CH2)mxe2x80x94Rd, where m represents an integer of 0 to 3 and Rd represents a cycloalkyl group having 3 to 6 carbon atoms which may be substituted with a straight or branched alkyl group having 1 to 3 carbon atoms; Rb represents xe2x80x94SO2xe2x80x94Re, where Re represents a straight or branched alkyl group having 1 to 3 carbon atoms; and Rc represents an aryl group which may have a substituent, a cycloalkyl group having 3 to 6 carbon atoms which may have a substituent, or a monocyclic heterocyclic group which may have a substituent) that selectively inhibits COX-2 is known from Japanese Patent Application Disclosure Hei No. 10-77266 (Japanese Patent Application Hei No. 9-24567).
The object of the present invention is to provide an indole derivative and a mono- or diazaindole derivative that have COX-2 inhibitory activity and are useful as pharmaceuticals, such as anti-inflammatory agents, etc.
As a result of conducting earnest research for the purpose of developing a compound that selectively or non-selectively inhibits COX-2 and has an anti-inflammatory action comparable to or higher than indometacin and other. existing NSAIDs, the inventors of the present application found that a compound represented by the general formula (1) has an excellent anti-inflammatory action and/or improved water solubility, making it useful as a pharmaceutical, thereby leading to completion of the present invention on the basis of this finding.
Accordingly, the present invention relates to a compound represented by the general formula (1): 
wherein Het represents a heterocyclic group which may be substituted;
A1 and A2 each independently represent xe2x80x94CHxe2x95x90or xe2x80x94Nxe2x95x90;
A3 represents xe2x80x94CH2xe2x80x94, xe2x80x94(Cxe2x95x90O)xe2x80x94 or xe2x80x94SO2xe2x80x94;
R1 represents a group selected from the following formulae: 
wherein A4 represents xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94 or xe2x80x94NHxe2x80x94;
R2 represents a straight or branched alkyl group having 1 to 3 carbon atoms;
n represents 0, 1 or 2, provided that when both A1 and A2 are xe2x80x94CHxe2x95x90, A3 represents xe2x80x94CH2xe2x80x94 or xe2x80x94SO2xe2x80x94,
or addition salts thereof with a pharmaceutically acceptable acid or base, or hydrates thereof.
In the definition of the compound represented by the general formula (1), a straight or branched alkyl group having 1 to 3 carbon atoms includes a methyl group, an ethyl group, an n-propyl group and an i-propyl group.
A heterocyclic group, which may be substituted, represented by Het is a 4- to 10-membered, monocyclic or condensed ring aliphatic or aromatic group containing 1, 2, 3 or 4 hetero atoms, which may be identical or different, such as an oxygen atom, a nitrogen atom and a sulfur atom. The substituent of the heterocyclic group includes, for example, a halogen atom, a straight or branched alkyl group having 1 to 4 carbon atoms (the group may be further substituted with a halogen atom), a straight or branched alkoxyl group having 1 to 4 carbon atoms (the group may be further substituted with a halogen atom), an oxo group, xe2x80x94S(O)pxe2x80x94R3 (in which p is an integer of 0 to 2 and R3 represents a straight or branched alkyl group having 1 to 3 carbon atoms), an amino group, a nitro group, a carboxyl group, xe2x80x94COOR4 (in which R4 represents a straight or branched alkyl group having 1 to 3 carbon atoms), xe2x80x94CONR5R6 (in which R5 and R6 may be the same or different and each represent a hydrogen atom or a straight or branched alkyl group having 1 to 3 carbon atoms), a cyano group and a hydroxyl group. Among them, a fluorine atom, a chlorine atom, a bromine atom, an iodine atom, a methyl group, an ethyl group, an n-propyl group, an i-propyl group, a t-butyl group, a trifluoromethyl group, a methoxy group, an ethoxy group, an oxo group, a methylthio group, a methanesulfonyl group, an ethanesulfonyl group, an amino group, a nitro group, a carboxyl group, a methoxycarbonyl group, a methylaminocarbonyl group, a cyano group and a hydroxyl group are preferred and the fluorine atom, the carboxyl group, the methyl group, the methoxycarbonyl group and the methylaminocarbonyl group are particularly preferred. The above heterocyclic group may be further substituted with 1 to 3, preferably 1 heterocyclic group. The heterocyclic group as the substituent in this case includes heterocyclic groups listed below, which may be substituted, represented by Het in the compound of the general formula (1). Among them, tetrazolyl (particularly 5-tetrazolyl) and triazolyl (particularly 1,2,3-triazol-4-yl and 1,2,4-triazol-3-yl) are preferred.
While the heterocyclic group in the definition of Het can be substituted with the above substituent, a nitrogen atom of the heterocyclic group can further be bonded with an oxygen atom to form N-oxide. Moreover, a nitrogen atom and a carbon atom of the heterocyclic group may be substituted with a straight or branched alkyl group having 1 to 4 carbon atoms. Such alkyl group includes a methyl group.
In the definition of the compound of the formula (1), Het is the heterocyclic group which may be substituted with the above substituent, that is, a 4- to 10-membered, monocyclic or condensed cyclic aliphatic or aromatic group containing 1, 2, 3 or 4 identical or different hetero atoms, such as an oxygen atom, a nitrogen atom and a sulfur atom, preferably a 4- to 6-membered monocyclic aliphatic or aromatic group containing 1, 2, 3 or 4 identical or different hetero atoms, such as an oxygen atom, a nitrogen atom and a sulfur atom.
Such heterocyclic group includes, for example, a group derived from a heterocyclic compound such as oxetane, furan, dihydrofuran, tetrahydrofuran, pyran, dihydropyran, tetrahydropyran, dioxole, thiophene, dihydrothiophene, tetrahydrothiophene, thiopyran, dihydrothiopyran, tetrahydrothiopyran, pyrrole, dihydropyrrole, pyrrolidine, pyridine, dihydropyridine, tetrahydropyridine, piperidine, pyrazole, 2-pyrazoline, pyrazolidine, imidazole, imidazolidine, pyrimidine, pyrazine, oxazoline, piperazine, 1,2,3-triazole, 1,2,4-triazole, tetrazole, isoxazole, 1,3-oxazole, 1,2,3-oxadiazole, 1,2,4-oxadiazole, 1,2,5-oxadiazole, 1,3,4-oxadiazole, 1,2-thiazole, 1,3-thiazole, 1,2,3-thiadiazole, 1,2,4-thiadiazole, 1,2,5-thiadiazole, 1,3,4-thiadiazole, 1,3-dioxolan, oxazolidine and morpholine. Among them, Het includes a 5- or 6-membered, monocyclic aliphatic heterocyclic group or aromatic heterocyclic group, which may be substituted with the above group, and contains 1, 2 or 3 identical or different hetero atoms selected from an oxygen atom, a nitrogen atom and a sulfur atom, and particularly includes a group which may be substituted with the above group, derived from furan, 1,3-thiazole, 1,3-oxazole, 1,3,4-oxadiazole, pyrimidine, tetrahydrofuran, 5,6-dihydropyran, pyridine, 1,2,4-triazole, 1,2,4-oxadiazole and tetrahydropyran.
Of Het having the heterocyclic group listed above, preferred is the compound of the general formula (1) in which Het is a 5- or 6-membered, monocyclic unsaturated aliphatic heterocyclic group or aromatic heterocyclic group, which may be substituted with the above group, and contains, identically or differently, 1, 2 or 3 nitrogen atoms and/or oxygen atoms and can further contain 1 sulfur atom. The compound of the general formula (1) in which Het is a group derived from furan, 1,3-thiazole, 1,3-oxazole, 1,3,4-oxadiazole, pyridine, pyrimidine or 5,6-dihydropyran, which may be substituted with the above group, is preferred in terms of activity. Of the compound of the above general formula (1), a compound in which the heterocyclic group of Het is substituted with a carboxyl group or a nitrogen atom of the nitrogen atom-containing heterocyclic group of Het is N-oxide is preferred in terms of water solubility or oral absorption.
Further, in a group: xe2x80x94(CH2)nxe2x80x94 bonded to the above Het group, n represents 0, 1 or 2, preferably 0 or 1.
In the definition of the compound represented by the general formula (1), while A1 and A2 each independently represent xe2x80x94CHxe2x95x90or xe2x80x94Nxe2x95x90, A1 is preferably xe2x80x94CHxe2x95x90.
Further, while R2 represents a straight or branched alkyl group having 1 to 3 carbon atoms, the group includes a methyl group, an ethyl group, an n-propyl group and an i-propyl group. Among them, a methyl group is preferred.
Furthermore, while A3 represents xe2x80x94CH2xe2x80x94, xe2x80x94(Cxe2x95x90O)xe2x80x94 or xe2x80x94SO2xe2x80x94, xe2x80x94CH2xe2x80x94 and xe2x80x94SO2xe2x80x94 are preferred and xe2x80x94CH2xe2x80x94 is particularly preferred. When A1 and A2 both represent xe2x80x94CHxe2x95x90, A3 represents xe2x80x94CH2xe2x80x94 or xe2x80x94SO2xe2x80x94.
While R1 is selected from 9 types of the group described in the definition of the general formula (1) as described above, particularly there may be mentioned a compound of the general formula (1) in which R1 is a 4-fluorophenyl group.
In the compound of the general formula (1), a group: R1xe2x80x94A3xe2x80x94 is preferably a 4-fluorobenzyl group.
Examples of xe2x80x94(CH2)n-Het in the general formula (1) of the compound according to the present invention are shown in the following Table 1 to 10:
Preferred xe2x80x94(CH2)n-Het includes a 1,3-thiazol-2-yl group, a 1,3-oxazol-2-yl group, a 1,3,4-oxadiazol-2-yl group, a 2-furyl group, a 2-pyridyl group, a 2-pyrimidinyl group, a 5-methylfuran-2-yl group, a 2-tetrahydrofuranyl group, a 5,6-dihydro-2H-4-pyranyl group, a 5-methylaminocarbonylpyridin-2-yl group and a 5-fluoropyrimidin-4-yl group.
The compound represented by the general formula (1) preferably includes the following:
a compound selected from
2-(2-furyl)-1-(4-fluorobenzyl)-5-methanesulfonyl-1H-pyrrolo[2,3-b]pyridine;
1-(4-fluorobenzyl)-5-methanesulfonyl-2-(thiazol-2-yl)indole;
1-(4-fluorobenzyl)-2-(oxazol-2-yl)-5-methanesulfonyl-1H-pyrrolo[2,3-b]pyridine;
1-(4-fluorobenzyl)-5-methanesulfonyl-2-([1,3,4]oxadiazol-2-yl)indole;
5-methanesulfonyl-2-(2-pyridyl)-1-(4-fluorobenzyl)-1H-pyrrolo[2,3-b]pyridine;
1-(4-fluorobenzyl)-5-methanesulfonyl-2-(2-pyrimidinyl)-1H-pyrrolo[2,3-b]pyridine;
1-cyclohexylmethyl-5-methanesulfonyl-2-(2-pyrimidinyl)-1H-pyrrolo[2,3-b]pyridine;
2-(2-furanyl)-1-(4-fluorobenzyl)-5-methanesulfonyl-indole;
1-cyclohexylmethyl-2-(2-furanyl)-5-methanesulfonyl-indole;
2-(2-furanyl)-5-methanesulfonyl-1-(2-pyridylmethyl)-1H-pyrrolo[2,3-b]pyridine;
1-(4-fluorobenzyl)-5-methanesulfonyl-2-(5-methylfuran-2-yl)-1H-pyrrolo[2,3-b]pyridine;
2-(2-furanyl)-1-cyclohexylmethyl-5-methanesulfonyl-1H-pyrrolo[2,3-b]pyridine;
2-(2-tetrahydrofuranyl)-1-(4-fluorobenzyl)-5-methanesulfonyl-indole;
2-(5,6-dihydro-2H-4-pyranyl)-1-(4-fluorobenzyl)-5-methanesulfonyl-indole;
1-(4-fluorobenzyl)-5-methanesulfonyl-2-(5-methoxycarbonylpyridin-2-yl)indole;
1-(4-fluorobenzyl)-2-(5-carboxypyridin-2-yl)-5-methanesulfonylindole;
1-(4-fluorobenzyl)-5-methanesulfonyl-2-(5-methylaminocarbonylpyridin-2-yl)indole;
1-(4-fluorobenzyl)-5-methanesulfonyl-2-(3-pyridylmethyl)indole;
1-(4-fluorobenzyl)-5-methanesulfonyl-2-(3-pyridyl)indole;
1-(4-fluorobenzyl)-5-methanesulfonyl-2-(1-oxy-3-pyridyl)indole;
1-(4-fluorobenzenesulfonyl)-5-methanesulfonyl-2-(thiazol-2-yl)indole;
1-(4-fluorobenzyl)-5-methanesulfonyl-2-(5-methyl-[1,2,4]triazol-3-yl)indole;
1-(4-fluorobenzyl-5-methanesulfonyl-2-(3-methyl-[1,2,4]oxadiazol-5-yl)indole;
1-(4-fluorobenzyl)-5-methanesulfonyl-2-(5-methyl-[1,2,4]oxadiazol-3-yl)indole;
1-(4-fluorobenzyl)-5-methanesulfonyl-2-(tetrahydropyran-4-yl)indole;
5-methanesulfonyl-2-(1-oxy-2-pyridyl)-1-(4-fluorobenzyl)-1H-pyrrolo[2,3-b]pyridine;
1-(4-fluorobenzyl)-5-methanesulfonyl-2-(2-thiazolylmethyl)indole;
6-(1-(4-fluorobenzyl)-5-methanesulfonyl-1H-pyrrolo[2,3-b]pyridin-2-yl)nicotinic acid methylamide;
2-(2-carboxyfuran-5-yl)-1-(4-fluorobenzyl)-5-methanesulfonyl-indole;
2-(2-carboxyfuran-5-ylmethyl)-1-(4-fluorobenzyl)-5-methanesulfonylindole;
1-(4-fluorobenzyl)-5-methanesulfonyl-2-(4-pyridyl)indole;
1-(4-fluorobenzyl)-5-methanesulfonyl-2-(1-oxy-4-pyridyl)indole;
1-(4-fluorobenzyl)-5-methanesulfonyl-2-([1,3,4]oxadiazol-2-yl)-1H-pyrrolo[2,3-b]pyridine;
5-(4-fluorobenzyl)-2-methanesulfonyl-6-(thiazol-2-yl)-5H-pyrrolo[2,3-b]pyrazine;
5-(4-fluorobenzyl)-2-methanesulfonyl-6-(oxazol-2-yl)-5H-pyrrolo[2,3-b]pyrazine;
1-(4-fluorobenzyl)-5-methanesulfonyl-2-(5-fluoropyrimidin-4-yl)-1H-pyrrolo[2,3-b]pyridine; and
1-(2,4-difluorobenzyl)-5-methanesulfonyl-2-([1,3,4]oxadiazol-2-yl)-1H-pyrrolo[2,3-b]pyridine, or addition salts thereof with a pharmaceutically acceptable acid or base, or hydrates thereof.
Among the above compounds, 1-(4-fluorobenzyl)-5-methanesulfonyl-2-(thiazol-2-yl)indole; 1-(4-fluorobenzyl)-2-(oxazol-2-yl)-5-methanesulfonyl-1H-pyrrolo[2,3-b]pyridine; and 1-(4-fluorobenzyl)-5-methanesulfonyl-2-([1,3,4]oxadiazol-2-yl)indole and addition salts thereof with a pharmaceutically acceptable acid or base, and hydrates thereof are particularly preferred.
The compound of the present invention can be prepared by the method of the reaction scheme 1 or 2 described below or the methods which are suitably partially modified according to the desired compound to be prepared, or any other suitable methods, starting from known compounds. The compound of the present invention can be also obtained by suitably applying specific preparation methods described in Examples.
Of the compounds of the present invention, the compound in which A3 is xe2x80x94CH2xe2x80x94 and n is 0 can be prepared based on the following reaction scheme 1 by using a reagent having a desired group. 
[wherein R3 represents a methyl group, a phenyl group or a 4-methylphenyl group; R4 represents a hydrogen atom or a trimethylsilyl group; Hal represents a halogen atom, such as a chlorine atom, a bromine atom and an iodine atom; and other symbols are as defined in the general formula (1)].
In the reaction scheme 1, the conversion of Compound 1 (for example, described in WO98/51667 and Japanese Patent Application Disclosure Hei No. 11-29553, Example III-1) to Compound 2 can be carried out by reacting Compound:1 with a compound R3SO2Cl (in which R3 represents a methyl group, a phenyl group or a 4-methylphenyl group) in the presence of a base, followed by base treatment and hydrolysis. The base employable with R3SO2Cl includes pyridine, 4-dimethylaminopyridine, triethylamine, tripropylamine, tributylamine and diisopropylethylamine, preferably pyridine. The reaction solvent employable includes dichloromethane, chloroform, 1,2-dichloroethane, benzene, toluene, xylene, tetrahydrofuran or 1,4-dioxane, whereas the reaction can be and is preferably carried out without any solvents. The reaction is carried out at 0 to 100xc2x0 C., preferably 10 to 80xc2x0 C. The base employable in hydrolysis includes potassium hydroxide, sodium hydroxide, lithium hydroxide, potassium carbonate, sodium carbonate and lithium carbonate, preferably potassium hydroxide. The reaction solvent employable in hydrolysis includes water, methanol, ethanol, isopropanol, tetrahydrofuran, 1, 4-dioxane and acetonitrile in a single form or a mixed solvent. A mixed-solvent of water, methanol and 1,4-dioxane is preferably used. The reaction is carried out at 0 to 100xc2x0 C., preferably 10 to 80xc2x0 C.
The conversion of Compound 2 to Compound 3 can be carried out by reacting Compound 2 with an acetylene compound R4xe2x80x94Cxe2x95x90C-Het (in which R4 represents a hydrogen atom or a trimethylsilyl group) having the desired group Het in the presence of a palladium catalyst, a copper reagent and a base. The palladium catalyst employable includes bis(triphenylphosphine)palladium chloride, bis(triphenylphosphine)palladium acetate, bis(acetonitrile)palladium chloride and bis(benzonitrile)palladium chloride, preferably bis (triphenylphosphine)palladium chloride. The copper reagent employable includes copper(0), copper(II) acetate, copper(I) bromide, copper(II) bromide, copper(I) chloride, copper(II) chloride, copper(I) iodide, copper(II) iodide, copper(I) oxide, copper(II) oxide and copper(II) sulfate, preferably copper(I) iodide. The base employable includes triethylamine, tripropylamine, tributylamine, diisopropylethylamine, triisobutylamine, diethylamine, dipropylamine, dibutylamine, potassium carbonate, sodium carbonate, sodium hydrogencarbonate and potassium hydrogencarbonate, preferably triethylamine. The reaction solvent employable includes 1,4-dioxane, N,N-dimethylformamide, acetonitrile, N,N-dimethylacetamide, tetrahydrofuran, dimethoxyethane, benzene, toluene and dimethyl sulfoxide. The reaction can also be carried out using no solvents. The reaction is preferably carried out using 1,4-dioxane or N,N-dimethylformamide, or using no solvents. The reaction is carried out at 15 to 150xc2x0 C., preferably 40 to 120xc2x0 C.
The conversion of Compound 3 to Compound 4 can be carried out by oxidizing Compound 3. The oxidizing agent employable includes OXONE (registered trademark), m-chloroperbenzoic acid, magnesium monoperoxyphthalate and so forth. As the reaction solvent, there may be used tetrahydtofuran, ether, dimethoxyethane, 1,4-dioxane, dichloromethane, chloroform, methanol, ethanol, water and so forth singly or in a form of mixed solvent. When OXONE is used, a mixed solvent of tetrahydrofuran and water or of tetrahydrofuran, methanol and water is preferably employed; when m-chloroperbenzoic acid is used, dichloromethane is preferably employed; and when magnesium monoperoxyphthalate is used, a mixed solvent of dichloromethane and methanol is preferably employed. The reaction is carried out at xe2x88x9210 to 60xc2x0 C., preferably 0 to 40xc2x0 C.
The oxidizing reaction can be carried out at any steps in the reaction scheme 1 when it satisfies the condition that it is conducted before the step of base treatment (including the corresponding steps) in the conversion of Compound 4 to Compound 5 described later.
The conversion of Compound 4 to Compound 5 c an be carried out by the base treatment of Compound 4 and elimination of the group xe2x80x94SO2R3. The base employable includes potassium hydroxide, sodium hydroxide, lithium hydroxide, potassium carbonate, sodium carbonate, lithium. carbonate and so forth, preferably potassium hydroxide. As the reaction solvent, there may be used water, methanol, ethanol, isopropanol, tetrahydrofuran, 1,4-dioxane, acetonitrile and so forth singly or in a form of mixed solvent. Preferred is methanol alone; a mixed solvent of water and methanol; a mixed solvent of water, 1,4-dioxane and tetrahydrofuran; or a mixed solvent of water, methanol and tetrahydrofuran. The reaction is carried out at 0 to 100xc2x0 C., preferably 15 to 100xc2x0 C.
The elimination reaction of the group xe2x80x94SO2R3 can be carried out at any steps in the reaction scheme 1 if conditions are satisfied such that it is carried out after the step of oxidation (including the corresponding steps) in the conversion of Compound 3 to Compound 4 described before and before the step of introducing the group R1CH2xe2x80x94 (including the corresponding steps) in the conversion of Compound 5 to Compound 6 described later. When the substituent at the position relative to the 5-position on the indole ring is R2O2Sxe2x80x94, the elimination reaction may occur accompanied by other reactions.
The conversion of Compound 5 to Compound 6 can be carried out by the base treatment of Compound 5, which is subsequently followed by the treatment with the compound R1CH2Hal having the desired group R1 (in which Hal represents a halogen atom, such as a chlorine atom, a bromine atom and an iodine atom) to introduce the group R1CH2xe2x80x94. The base employable includes sodium hydride, potassium hydride, sodium methoxide, sodium ethoxide, potassium-t-butoxide, lithium diisopropylamide, lithium bis(trimethylsilyl)amide and so forth, preferably sodium hydride or lithium diisopropylamide. The reaction solvent employable includes N,N-dimethylformamide, N,N-dimethylacetamide, tetrahydrofuran, dimethoxyethane, dimethyl sulfoxide, ether and so forth, preferably N,N-dimethylformamide or tetrahydrofuran. The reaction is carried out at xe2x88x9278 to 50xc2x0 C., preferably xe2x88x9278 to 30xc2x0 C.
When the compound R1COHal or R1SO2Hal is used instead of the compound R1CH2Hal, the compound of the general formula (1) (wherein A3 represents xe2x80x94(Cxe2x95x90O)xe2x80x94 or xe2x80x94SO2xe2x80x94) can be obtained. The base, the reaction solvent and reaction temperature employable here are similar to those used in the introduction of the group R1CH2xe2x80x94.
Of the compounds according to the present invention, the compound in which A3 is xe2x80x94CH2xe2x80x94 and n is 1 can be prepared based on the following reaction scheme 2 by using the reagent having the desired group. 
[wherein R3 represents a methyl group, a phenyl group or a 4-methylphenyl group; Hal represents a halogen atom, such as a chlorine atom, a bromine atom and an iodine atom; and other symbols are as defined in the general formula (1)].
In the reaction scheme 2, conversion of Compound 7 (described in WO98/51667 and Example I-1 of Japanese Patent Application Disclosure Hei No. 11-29553) to Compound 8 can be carried out by reacting Compound 7, after the base treatment, with aldehyde CHO-Het having the desired group Het to bind the group Het to Compound 7 via a methylene group. The base employable includes lithium diisopropylamide, lithium bis(trimethylsilyl)amide, n-butyl lithium, sec-butyl lithium, tert-butyl lithium and so forth, preferably lithium diisopropylamide and n-butyl lithium. The reaction solvent employable includes tetrahydrofuran, ether and so forth, preferably tetrahydrofuran. The reaction is carried out at xe2x88x9278 to 50xc2x0 C., preferably xe2x88x9278 to 30xc2x0 C.
By using the compound having a formyl group at the position corresponding to the 2-position in the indole ring and the compound Het-Hal substituted with a halogen atom, such as a chlorine atom, a bromine atom and an iodine atom, Compound 8 can be also obtained by subjecting them to the steps similar to those of the conversion reaction of Compound 7 to Compound 8.
Further, the compound represented by the formula (1), wherein n is 2, can be obtained by using the compound CHOxe2x80x94CH2-Het instead of the compound CHO-Het.
Furthermore, the compound represented by the formula (1), wherein n is 0, can be obtained by using Het having the xe2x80x94(Cxe2x95x90O)xe2x80x94 partial structure instead of the compound CHO-Het.
The conversion of Compound 8 to Compound 9 can be carried out by oxidizing Compound 8 to be ketones, followed by reduction with hydrazine, or by catalytic reduction of Compound 8. The oxidizing agent employable for oxidization to allow Compound 8 to be ketones include Des Martin reagent (1,1,1-tris(acetyloxy)-1,1-dihydro-1,2-benziodoxol-3 (1H)-one), manganese dioxide, chromic acid, pyridinium dichromate, pyridinium chlorochromate, the combination of dimethyl sulfoxide, oxalyl chloride and triethylamine and so forth, preferably Des Martin reagent (1,1,1-tris(acetyloxy)-1,1-dihydro-1,2-benziodoxol-3 (1H)-one) and manganese dioxide. The reaction solvent employable includes dichloromethane, chloroform, 1,2-dichloroethane, acetone and so forth, preferably dichloromethane. The reaction is carried out at xe2x88x9278 to 50xc2x0 C., preferably xe2x88x9278 to 30xc2x0 C. The reduction with hydrazine can be carried out in the presence of a base. The base employable includes potassium hydroxide, sodium hydroxide, lithium hydroxide and so forth, preferably potassium hydroxide. The reaction solvent employable includes ethylene glycol, ethanol, methanol, isopropanol and so forth, preferably ethylene glycol. The reaction is carried out at 15 to 150xc2x0 C., preferably 40 to 120xc2x0 C. The catalyst employable in the catalytic reduction includes palladium carbon, palladium hydroxide, palladium black and so forth, preferably palladium carbon. As the reaction solvent, ethanol, methanol, ethyl acetate and so forth are used in the presence or absence of acetic acid, and ethanol is preferably used in the presence of acetic acid. The reaction is carried out at 0 to 80xc2x0 C., preferably 15 to 60xc2x0 C. under a pressure of 1 to 5 atm, preferably 1 atm.
Conversion of Compound 9 to Compound 10 is carried out by oxidizing Compound 9. The oxidizing agent employable includes OXONE (registered trademark), m-chloroperbenzoic acid, magnesium monoperoxyphthalate and so forth. As the reaction solvent, there may be used tetrahydrofuran, ether, dimethoxyethane, 1,4-dioxane, dichloromethane, chloroform, methanol, ethanol, water and so forth singly or in the form of mixed solvent. When OXONE is used, a mixed solvent of tetrahydrofuran and water or of tetrahydrofuran, methanol and water is preferably employed; when m-chloroperbenzoic acid is used, dichloromethane is preferably employed, and when magnesium monoperoxyphthalate is used, a mixed solvent of dichloromethane and methanol is preferably employed. The reaction is carried out at xe2x88x9210 to 60xc2x0 C., preferably 0 to 40xc2x0 C.
The conversion step of Compound 8 to Compound 9 and that of Compound 9 to Compound 10 are interchangeable.
Conversion of Compound 10 to Compound 11 can be carried out by the base treatment of Compound 10. The base employable includes potassium hydroxide, sodium hydroxide, lithium hydroxide, potassium carbonate, sodium carbonate, lithium carbonate and so forth, preferably potassium hydroxide. As the reaction solvent, there may be used water, methanol, ethanol, isopropanol, tetrahydrofuran, 1,4-dioxane, acetonitrile and so forth singly or in the form of mixed solvent. Preferred is methanol alone; a mixed solvent of water and methanol; a mixed solvent of water, 1,4-dioxane and tetrahydrofuran; or a mixed solvent of water, methanol and tetrahydrofuran. The reaction is carried out at 0 to 100xc2x0 C., preferably 15 to 100xc2x0 C.
Conversion of Compound 11 to Compound 12 can be carried out by the base treatment of Compound 11, which is subsequently followed by the treatment with the compound R1CH2Hal (in which Hal represents a halogen atom, such as a chlorine atom, a bromine atom and an iodine atom) having the desired group R1. The base employable includes sodium hydride, potassium hydride, sodium methoxide, sodium ethoxide, potassium-t-butoxide, lithium diisopropylamide, lithium bis(trimethylsilyl)amide and so forth, preferably sodium hydride or lithium diisopropylamide. The reaction solvent employable includes N,N-dimethylformamide, N,N-dimethylacetamide, tetrahydrofuran, dimethoxyethane, dimethyl sulfoxide, ether and so forth, preferably N,N-dimethylformamide or tetrahydrofuran. The reaction is carried out at xe2x88x9278 to 50xc2x0 C., preferably xe2x88x9278 to 30xc2x0 C. when the compound R1COHal or R1SO2Hal is used instead of the compound R1CH2Hal, the compound of the general formula (1) (wherein A3 is xe2x80x94(Cxe2x95x90O)xe2x80x94 or xe2x80x94SO2xe2x80x94, respectively) can be obtained. The base, the reaction solvent and reaction temperature employable here are similar to those used in the introduction of the group R1CH2xe2x80x94.
The heterocyclic group represented by Het of Compound 6 or Compound 12 represented by the general formula (1) obtained in the reaction scheme 1 or 2, can be converted by the following methods.
The conversion of a double bond in Het to a single bond can be carried out by catalytic reduction of the compound having the double bond. The catalyst employable in the catalytic reduction includes palladium carbon, palladium hydroxide, palladium black and so forth, preferably palladium carbon. As the reaction solvent, there may be used ethanol, methanol, ethyl acetate, acetic acid and so forth singly or in the form of mixed solvent, preferabley ethanol. The reaction is carried out at 0 to 80xc2x0 C., preferably 15 to 60xc2x0 C.
Conversion of an alkyl ester to other alkyl esters in the case where Het has a substituent xe2x80x94COOR4 (in which R4 represents a straight or branched alkyl group having 1 to 3 carbon atoms) can be carried out by effecting a base on the alkyl ester in an alcohol having the desired alkyl group. The base employable includes potassium hydroxide, sodium hydroxide, lithium hydroxide, potassium carbonate, sodium carbonate, lithium carbonate and so forth, preferably potassium hydroxide. As the reaction solvent, there may be used methanol, ethanol, isopropanol, tetrahydrofuran, 1,4-dioxane, acetonitrile and so forth singly or in the form of mixed solvent, preferably methanol. The reaction is carried out at 0 to 100xc2x0 C., preferably 15 to 100xc2x0 C.
Conversion of an alkyl ester to a carboxylic acid in the case where Het has the substituent xe2x80x94COOR4 can be carried out by effecting a base on the alkyl ester. The base employable includes potassium hydroxide, sodium hydroxide, lithium hydroxide, potassium carbonate, sodium carbonate, lithium carbonate and so forth, preferably potassium hydroxide and lithium hydroxide. As the reaction solvent, there may be used water, methanol, ethanol, isopropanol, tetrahydrofuran, 1,4-dioxane, acetonitrile and so forth singly or in the form of mixed solvent, preferabley methanol. The reaction is carried out at 0 to 100xc2x0 C., preferably 15 to 100xc2x0 C.
Conversion of a carboxyl group to the group xe2x80x94CONR5R6 in the case where Het has the substituent, a carboxyl group (in which R5 and R6 may be the same or different and each represent a hydrogen atom or a straight or branched alkyl group having 1 to 3 carbon atoms) can be carried out by converting the carboxyl group to an acid chloride, and subsequently reacting it with amine HNR5R6 having the desired group in the presence or absence of a base. The reagent employable for the conversion to the acid chloride includes thionyl chloride, oxalyl chloride, phosphorous oxychloride, phosphorous pentachloride and so forth, preferably thionyl chloride. The reaction is carried out at 0 to 120xc2x0 C., preferably 20 to 100xc2x0 C. The base employable in the reaction with amine includes triethylamine, diisopropylethylamine, pyridine and so forth, preferably triethylamine. As the reaction solvent employable in the reaction with amine, there may be used methanol, ethanol, tetrahydrofuran, dioxane, dimethoxyethane, dichloromethane, chloroform and so forth singly or in the form of mixed solvent, preferably tetrahydrofuran. The reaction is carried out at xe2x88x9210 to 50xc2x0 C., preferably 0 to 30xc2x0 C.
Further, the conversion of the carboxyl group to the group xe2x80x94CONR5R6 in the case where Het has the substituent, a carboxyl group can be carried out by treating the carboxyl group with a condensation agent and subsequently with amine HNR5R6 having the desired group. The condensation agent employable includes 1,1xe2x80x2-carbonyldiimidazole, benzotriazol-1-yloxy-tris(dimethylamino)phosphonium hexafluorophosphate, dicyclohexylcarbodiimide, diethyl cyanide phosphate and so forth; preferably 1,1xe2x80x2-carbonyldiimidazole or benzotriazol-1-yloxy-tris(dimethylamino)phosphonium hexafluorophosphate. As the reaction solvent, there may be used methanol, ethanol, tetrahydrofuran, dioxane, dimethoxyethane, dichloromethane, chloroform and so forth singly or in the form of mixed solvent, preferably tetrahydrofuran or dichloromethane. The reaction is carried out at xe2x88x9210 to 50xc2x0 C., preferably 0 to 30xc2x0 C.
Furthermore, the conversion of the carboxyl group to the group xe2x80x94CONR5R6 in the case where Het has the substituent, a carboxyl group can be carried by treating the carboxyl group with chlorocarbonate and a base and subsequently with an amine HNR5R6 having the desired group. The chlorocarbonate employable includes methyl chlorocarbonate, ethyl chlorocarbonate and so forth, preferably ethyl chlorocarbonate. The base employable includes triethylamine, diisopropylethylamine, pyridine and so forth, preferably triethylamine. As the reaction solvent, there may be used tetrahydrofuran, dioxane, dimethoxyethane, dichloromethane, chloroform and so forth sigly or in the form of mixed solvent, preferably tetrahydrofuran. The reaction is carried out at xe2x88x9210 to 50xc2x0 C., preferably 0 to 30xc2x0 C.
Conversion to pyridine N-oxide in the case where Het is a group derived from pyridine can be carried out by oxidizing the pyridine derivative. The oxidizing agent employable includes m-chloroperbenzoic acid, magnesium monoperoxyphthalate and so forth. As the reaction solvent, there may be used dichloromethane, chloroform, 1,2-dichloroethane, methanol, ethanol and so forth singly or in the form of mixed solvent. When m-chloroperbenzoic acid is used, dichloromethane is preferably employed, and when magnesium monoperoxyphthalate is used, a mixed solvent of dichloromethane and methanol is preferably employed. The reaction is carried out at xe2x88x9210 to 60xc2x0 C., preferably 0 to 40xc2x0 C.
The reagent used in the above reaction schemes 1 and 2 is known or can be synthesized according to the known methods or methods which can be easily attained by those skilled in the art from the known methods. Further, they can be also synthesized by referring to the method described in Examples of the present application.
The compound of the present invention has a cyclooxygenase 2 (COX-2) inhibitory action and is useful as an anti-inflammatory agent. The compound of the present invention can be administered orally or parenterally. The dosage is 3 to 150 mg/kg per day for an oral administration and 1 to 50 mg/kg per day for a parenteral administration.
When the compound is administered as a pharmaceutical, it can be prepared using usual formulation techniques and used in a dosage form of solid or liquid, such as tablets, capsules, powders, granules, suppositories, solution, suspension or emulsion.
Further, in this case, additive components which are customarily used for pharmaceutical preparations such as excipients, disintegrators, lubricants, binders, preservatives, stabilizers, osmotic pressure regulating agents and so forth can be used.
An example of these additive components include, glucose, lactose, starches, carboxymethylcellulose, magnesium stearate, talc, liquid paraffin, polyvinyl alcohol, vegetable oil, polyalkylene glycol and so forth. Other pharmaceutical ingredients can be also included.